The invention relates to tetrahydropyridoethers for the treatment of AMD and claims the priority of the European Patent Application 08 000 761.0 of Jan. 16, 2008.
Age-related macular degeneration (AMD) is the main cause of blindness in the western world (Bird A C, Bressler N M, Bressler S B, Chisholm I H, Coscas G, Davis M D, de J P, Klaver C C, Klein B E, Klein R (1995) International classification and grading system for age-related maculopathy and age-related macular degeneration: Surv. Ophthalmol 39: 367-374). About 30 million people suffer from age-related macula degeneration (AMD), which leads to a loss of central vision.
The macula is the most important part of the retina. The retinal pigment endothelium (RPE) is essential for retinal function. In healthy eyes, undisturbed transport of metabolites takes place between photoreceptors and the RPE-choroid. Accumulation of material between Bruch's membrane and the RPE inhibits the transport of metabolites. Years of daily phagocytosis of the shed photoreceptor tips by RPE are thought eventually to take their toll in some individuals.
Over time, lipofuscin accumulates in the aging RPE until, in some cases, the cells are virtually engorged with this material and function is almost certainly compromised. It is generally accepted that this aging process is a causative factor in age-related macular degeneration.
Melanin
Optical measurements of the pigments of the RPE and choroid have been made in human autopsy eyes varying in age between 2 weeks and 90 years old. The choroidal melanin content increased from the periphery to the posterior pole. The RPE melanin concentration decreased from the periphery to the posterior pole with an increase in the macula. The amount of RPE Lipofuscin increased from the periphery to the posterior pole with a consistent dip at the fovea. In humans there is an inverse relationship between RPE lipofuscin concentration and RPE melanin concentration.
A biochemical examination has been carried out on the lipofuscin content, lysosomal enzyme activities and melanin level in the retina and choroid of normal human eyes. The melanin level was two to three times higher in the macular RPE and choroid than in other areas. Blue-light-induced photoreactivity of melanosomes increases with age, perhaps providing a source of reactive oxygen species and leading to depletion of vital cellular reductants, which, together with lipofuscin, may contribute to cellular dysfunction (Rozanowska M, Korytowsky W, Rozanowsky B, Skumatz C, Boulton M G, Burke J M, Sarna T Photoreactivity of aged human RPE melanosomes: a comparison with lipofuscin. Invest Ophthalmol Vis Sci 2002, 43, 2088-96).
Lipofuscin
Lipofuscin is a pigment that is formed in tissues with high oxidative stress (heart, liver, brain. eye) (Terman A, Brunk U T (1998) Lipofuscin: Mechanisms of formation and increase with age. APMIS 106: 265-276) Lipofuscin, also called age pigment, is a brown-yellow, electron-dense, autofluorescent material that accumulates progressively over time in lysosomes of postmitotic cells, such as neurons and cardiac myocytes and the RPE. The exact mechanisms behind this accumulation are still unclear. It can be detected histologically by its autofluorescence properties. The origin of lipofuscin in the RPE is still under debate (Kennedy C J, Rakoczy P E, Constable I J (1995) Lipofuscin of the retinal pigment epithelium: a review. Eye 9: 763-771). Numerous studies indicate that the formation of lipofuscin is due to the oxidative alteration of macromolecules by oxygen-derived free radicals generated in reactions catalyzed by redox-active iron of low molecular weight. Two principal explanations for the increase of lipofuscin with age have been suggested. The first one is based on the notion that lipofuscin is not totally eliminated (either by degradation or exocytosis) even at a young age, and, thus, accumulates in postmitotic cells as a function of time. Since oxidative reactions are obligatory for life, they would act as age-independent enhancers of lipofuscin accumulation, as well as of many other manifestations of senescence. The second explanation is that the increase of lipofuscin is an effect of aging, caused by an age-related enhancement of autophagocytosis, a decline in intralysosomal degradation, and/or a decrease in exocytosis. No reports state that lipofuscin can be degraded or exocytosed by RPE cells. In the eye, lipofuscin accumulates with age, especially in the RPE, and occupies a considerable part of the cell volume in elderly persons. Lipofuscin content, expressed as fluorescence intensity, in the macular retinal pigment epithelium (RPE) and choroid was two to three times higher than in other areas, and increased with aging.
Interestingly, there is an association of melanin and lipofuscin in the RPE. By use of enzyme cytochemistry, fluorescence microscopy, and lipid extraction, two types of melanin-containing complex granules have been identified: melanin with a cortex of lipofuscin (melanolipofuscin and melanin with a cortex of non-lipid, enzyme reactive material (melanolysosomes).
Lipofuscin and aged melanin in the RPE can generate oxygen radicals, and both are believed to be involved in making the RPE dysfunctional. The more lipofuscin the RPE at the margins of the geographic atrophy contains, the quicker the atrophy will progress (Holz et al. (2007) Am J Ophthalmol 143; 4639; Schmitz-Valckenberg et al 2006; IOVS 47:2648).
AMD
This correlation is well accepted in ophthalmology. If the progressing atrophy (AMD) reaches the macula, the patients become legally blind. Two forms exist: Wet AMD is characterized by neovascularization whereas dry AMD leads to geographic atrophy of the RPE and retina. Macular degeneration in both forms is associated with an accumulation of lipofuscin and melano-lipofuscin (Feeney L (1978) Lipofuscin and melanin of human retinal pigment epithelium. Fluorescence, enzyme cytochemical and ultrastructural studies. Invest. Ophthalmol. Vis. Sci. 17: 583-600), an increase in large deposits between the RPE cell layer and the Bruch's membrane (called drusen).
A high cost anti-VEGF therapy (Ranibizumab) has been developed against wet AMD.
80 to 85% of the AMD patients have dry AMD, for which no treatment modality currently exists.
It is consequently an object of the invention to provide a compound for the treatment of AMD, especially for dry AMD.